AA antifungals

Question 1

What are some modes of action of antifungals

Answer 1

Membrane disrupting agents
* Amphotericin B
* Nystatin
Ergosterol synthesis inhibitors
* Azoles, allylamines, morpholines
Nucleic acid inhibitor
* Flucytosine
Glucan synthesis inhibitors
* Echinocandins
Anti-mitotic
* Griseofulvin

Question 2

What are amphotericin B

Answer 2

Binds to ergosterol causing intercalation of the cell membrane
o Leakage of intracellular cations = cell death

Question 3

How does amphotericin B cause nephrotoxicity

Answer 3

Direct damage to distal tubule membranes = wasting of Na, K and Mg ions
Constriction of afferent arterioles = decreased GFR
Positive feedback loop

Question 4

What are some resistance to ampothericin B

Answer 4

• Defects in the ERG3 gene
• Deletion/mutation in the ERG6 gene
• AmB (R) mediated by increase catalase activity

Question 5

What are azoles mechanism of action

Answer 5

Accumulation of toxic sterols in cell membrane
o Inhibition of 14-ɑ-demethylase

Question 6

What are some examples of azoles

Answer 6

Fluconazole
- Uses
○ Invasive candidiasis
○ Cryptococcal disease
○ Other selected yeasts
○ NO activity against moulds
Good penetration into CSF and urine

Voriconazole
- Uses
○ Against aspergillosis
○ Invasive MDR - candidiasis
○ Other inherently moulds
- Available IV + PO
Good penetration inf CSF, poor in urine

Isavuconazole

Question 7

What are echinocandins (EC)

Answer 7

Inhibit glucan synthase enzyme
- Fungicidal
○ Candida spp
- Fungistatic
○ Aspergillus spp
Inhibition of glucan synthase = depletion of glucans in cell wall

Question 8

What are some resistance to azole

Answer 8

• Target enzyme modification
  ○ Mutations in ERG11 –> gene for synthesis of demethylase
  ○ Modification of the C-a-sterol demethylase enzymes
• Ergosterol biosynthesis pathway defects
• Efflux pumps
  ○ In CDR genes –> ATP binding cassette
  ○ MDR genes - major facilitators
• Decrease drug import
• Increase drug processing
• Up-regulation of target enzyme
  ○ Have higher intracellular concentration of ERG11 protein
• Bypass of metabolic pathways
  ○ Depletion of ergosterol + accumulation of toxic products = cell growth arrest